Trial Information

A Phase III Randomised Study to Investigate the Use of Adoptive Cellular Therapy (ACT) in Combination With Conventional Antiviral Drug Therapy for the Treatment of CMV Reactivation Episodes in Patients Following Allogeneic Haematopoietic Stem Cell Transplant

As with other herpes viruses, CMV infection is thought to result most frequently from
reactivation of latent virus. Transmission of the virus can also occur from donor marrow
infusion or from allogeneic red cell, leukocyte or platelet transfusions. In an allogeneic
haematopoietic stem cell (bone marrow) transplant patient who is CMV seropositive or
receiving a transplant from a donor who is CMV seropositive, CMV frequently reactivates and
disease resulting from the progression of infection is a major cause of infectious morbidity
and mortality. CMV infection is a consequence both of the immunosuppression these patients
receive and may also reflect delayed immune reconstitution in these patients following
transplant.

Existing evidence suggests that adoptive cellular therapy can be an effective approach for
treating viral reactivation following allo HSCT, with a minimal risk of inducing GVHD. The
major advantage to the patient is likely to be avoidance of extended periods of therapy with
antiviral medications that have significant associated morbidities, and sometimes require
inpatient care. A proof of efficacy in the sibling donor setting would strengthen the case
for extending the therapy to the unrelated donor setting, where both potential risks and
benefits are greater. From a pharmacoeconomic viewpoint, the avoidance of the costs
associated with these treatment episodes could offset the costs of adoptive cellular
therapy. A number of issues remain unresolved. These include the relative contributions of
transferred CD4+ and CD8+ T cell populations (which may have direct relevance to the best
approach for selection), the issue of whether adoptive cellular therapy improves outcomes in
a randomised setting, and equally importantly, the issue of whether such immunotherapies can
be delivered outside of the setting of a few academic institutions on a multicentre basis.

These considerations emphasise the importance of undertaking a randomised phase III study of
prophylactic adoptive cellular therapy for CMV following T cell depleted allogeneic HSCT
from a sibling donor (CMV~IMPACT). There are multiple methods for T cell depletion
available, and differences between them will likely have an effect on immune reconstitution.
In order to avoid this confounding influence the study will be restricted to patients
receiving alemtuzumab-containing conditioning protocols.

In summary, this study is a multicentre, prospective, controlled, open-label 3 arm
randomized study comparing 'best-available' standard anti-viral monitoring and therapy
alone, with 'best available'anti-viral monitoring and therapy plus prophylactic adoptive
cellular therapy (ACT) with cells selected by either the Gamma Catch or Multimer Selection
techniques. Patients will be randomised to:

A. Standard best available antiviral drug therapy alone B. Immunoprophylactic (Day 27) ACT
prepared using Gamma Catch Selection in combination with standard best available antiviral
drug therapy C. Immunoprophylactic (Day 27) ACT prepared using Multimer Selection in
combination with standard best available antiviral drug therapy

The study will test the hypothesis that CMV-specific ACT based upon a prescribed T-cell
dose/kg recipient body weight, can augment the impaired CMV immune function post-transplant
and reduce the number of recurrent reactivations in patients following a primary
reactivation event (and thereby reduce the requirement for antiviral drug therapy) without
causing an increase in GVHD.

Individual groups will be compared for duration of antiviral therapy and number of
reactivation episodes, plus GVHD incidence. Similar analyses will be performed for adoptive
cellular therapy versus no therapy (i.e. (B+C) versus A)